Appropriate Use of Genetic Testing in Congenital Heart Disease Patients

  • Seiji Ito
  • Kimberly A. Chapman
  • Monisha Kisling
  • Anitha S. John
Congenital Heart Disease (RA Krasuski, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Congenital Heart Disease


Purpose of Review

Congenital heart disease (CHD) remains the most common birth defect, occurring in 1% of all births. Although the exact etiology of CHD is still largely unknown, it is thought to be an interaction of genetic and non-genetic factors. The purposes of this review are to summarize recent advances in CHD genetics and testing and to present a suggested algorithm for appropriate use of genetic testing in patients with CHD.

Recent Findings

Advances in genetic testing technology are rapidly expanding the options for screening and are providing further insights into the genetic and molecular background of non-syndromic CHD. As the field advances, the role of the geneticist and genetic counselor will continue to expand as the testing becomes more complex and interpretation of results becomes increasingly challenging.


Coordination of practice between cardiologists and geneticists using a shared clinical structure is essential and will help improve cost utilization and facilitate individualized patient care.


Congenital heart disease Genetic testing Genetic counseling 

Supplementary material

11886_2017_834_MOESM1_ESM.docx (291 kb)
ESM 1Appendix Table 1. Easily internet accessible genetic resources (not necessarily all inclusive). Appendix Table 2. Genetic testing types and strengths and weakness. Appendix Table 3. Genetic changes identified to have CHD and some of these differences. (DOCX 290 kb)


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39(12):1890–900.CrossRefPubMedGoogle Scholar
  2. 2.
    Dray EM, Marelli AJ. Adult congenital heart disease: scope of the problem. Cardiol Clin. 2015;33(4):503. doi:10.1016/j.ccl.2015.07.001. –12–vii.CrossRefGoogle Scholar
  3. 3.
    Patel SS, Burns TL. Nongenetic risk factors and congenital heart defects. Pediatr Cardiol. 2013;34:1535–55. doi:10.1007/s00246-013-0775-4.CrossRefPubMedGoogle Scholar
  4. 4.
    Pierpont ME, Basson CT, Benson DW, Gelb BD, Giglia TM, Goldmuntz E, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115(23):3015–38.CrossRefPubMedGoogle Scholar
  5. 5.
    Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace. 2011;13:1077–109. doi:10.1093/europace/eur245.CrossRefPubMedGoogle Scholar
  6. 6.
    Manning M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12(11):742–5. doi:10.1097/GIM.0b013e3181f8baad.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Pediatric Cardiac Genomics Consortium, Writing Committee, Gelb B, Brueckner M, Chung W, Kaltman J, et al. The Congenital Heart Disease Genetic Network Study: rationale, design, and early results. Circ Res. 2013;112(4):698–706. doi:10.1161/CIRCRESAHA.111.300297.CrossRefGoogle Scholar
  8. 8.
    • Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013;498(7453):220–3. doi:10.1038/nature12141. This study used exome sequencing and identified de novo mutations in probands with severe CHD and no first-degree relative with identified structural heart disease.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ferencz C, Boughman JA, Neill CA, Brenner JI, Perry LW, Group TB-WIS. Congenital cardiovascular malformations: questions on inheritance. J Am Coll Cardiol. 1989;14(3):756–63.CrossRefPubMedGoogle Scholar
  10. 10.
    Meberg A, Hals J, Thaulow E. Congenital heart defects—chromosomal anomalies, syndromes and extracardiac malformations. Acta Paediatr. 2007;96(8):1142–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Blue GM, Kirk EP, Sholler GF, Harvey RP, Winlaw DS. Congenital heart disease: current knowledge about causes and inheritance. Med J Aust. 2012;197(3):155–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Glessner JT, Bick AG, Ito K, Homsy JG, Rodriguez-Murillo L, Fromer M, et al. Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Circ Res. 2014;115(10):884–96.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Blue GM, Kirk EP, Giannoulatou E, Dunwoodie SL, Ho JWK, Hilton DCK, et al. Targeted next-generation sequencing identifies pathogenic variants in familial congenital heart disease. J Am Coll Cardiol. 2014;64(23):2498–506. doi:10.1016/j.jacc.2014.09.048.CrossRefPubMedGoogle Scholar
  14. 14.
    •• Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science. 2015;350(6265):1262–6. This study showed higher rate of de novo gene mutation in proteins highly expressed in developing heart and brain among patients with CHD, neurodevelopmental disabilities, and extracardiac congenital anomalies. Further more, it showed mutations in the same genes were shared at high rates between patients with neurodevelopmental disabilities and CHD.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Connor JA, Hinton RB, Miller EM, Sund KL, Ruschman JG, Ware SM. Genetic testing practices in infants with congenital heart disease. Congenit Heart Dis. 2014;9(2):158–67. doi:10.1111/chd.12112.CrossRefPubMedGoogle Scholar
  16. 16.
    Buckley JR, Kavarana MN, Chowdhury SM, Scheurer MA. Current practice and utility of chromosome microarray analysis in infants undergoing cardiac surgery. Congenit Heart Dis. 2015;10(3):E131–8. doi:10.1111/chd.12241.CrossRefPubMedGoogle Scholar
  17. 17.
    Chen MY, Chiu SN, Wang JK, Lu CW, Lin MT, Chang CI, et al. Genetic syndromes and outcome after surgical repair of pulmonary atresia and ventricular septal defect. Ann Thorac Surg. 2012;94(5):1627–33. doi:10.1016/j.athoracsur.2012.06.063.CrossRefPubMedGoogle Scholar
  18. 18.
    Kelle AM, Qureshi MY, Olson TM, Eidem BW, O’Leary PW. Familial incidence of cardiovascular malformations in hypoplastic left heart syndrome. Am J Cardiol. 2015;116(11):1762–6. doi:10.1016/j.amjcard.2015.08.045.CrossRefPubMedGoogle Scholar
  19. 19.
    Oyen N, Poulsen G, Boyd HA, Wohlfahrt J, Jensen PKA, Melbye M. Recurrence of congenital heart defects in families. Circulation. 2009;120(4):295–301. doi:10.1161/CIRCULATIONAHA.109.857987.CrossRefPubMedGoogle Scholar
  20. 20.
    Calcagni G, Digilio MC, Sarkozy A, Dallapiccola B, Marino B. Familial recurrence of congenital heart disease: an overview and review of the literature. Eur J Pediatr. 2007;166(2):111–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Nora JJ. From generational studies to a multilevel genetic-environmental interaction. J Am Coll Cardiol. 1994;23(6):1468–71.CrossRefPubMedGoogle Scholar
  22. 22.
    Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease): developed in collaboration with the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2008;118(23):e714–833.CrossRefPubMedGoogle Scholar
  23. 23.
    Allen HD, Driscoll DJ, Shaddy RE, Feltes TF, editors. Moss and Adams’ heart disease in infants, children, and adolescents: including the fetus and young adult, 8th edition. Philadelphia (PA): Lippincott Williams & Wilkins; 2013Google Scholar
  24. 24.
    Allanson JE, Roberts AE. Noonan Syndrome. 2001 Nov 15 [Updated 2016 Feb 25]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016Google Scholar
  25. 25.
    Wong JT, Chan DK, Wong KY, Tan M, Rudduck C, Tien SL. Smith–Magenis syndrome and cyanotic congenital heart disease: a case report. Clin Dysmorphol. 2003;12:73–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Lalani SR, Hefner MA, Belmont JW, et al. CHARGE Syndrome. 2006 Oct 2 [Updated 2012 Feb 2]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016Google Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Seiji Ito
    • 1
  • Kimberly A. Chapman
    • 2
  • Monisha Kisling
    • 2
  • Anitha S. John
    • 1
  1. 1.Division of Pediatric CardiologyChildren’s National Health SystemWashingtonUSA
  2. 2.Division of Genetics and MetabolismChildren’s National Health SystemWashingtonUSA

Personalised recommendations